International journal of toxicology
January 31, 2026
Amir Lotfi, Samantha Sparapani, Mylène Pouliot et al.
5-MeO-DMT, a serotonin receptor agonist being developed for major depression, was tested for seizure risk in beagle dogs. Eight dogs received intranasal doses of 0.5, 1.0, and 1.5 mg/kg/day for nine days. Continuous EEG monitoring showed no seizures or epileptiform discharges at any dose, despite dose-dependent behavioral signs of serotonergic stimulation such as head shaking, tremors, and dilated pupils. These signs correlated with peak plasma levels and resolved within an hour. In a canine model sensitive to serotonergic drug-induced seizures, 5-MeO-DMT did not induce seizures, indicating low seizure liability.
Cureus
January 31, 2026
Lukasz Siwek, Marta Nowocien, Barbara Balajewicz et al.
Psilocybin, a psychoactive compound from Psilocybe mushrooms that activates serotonergic receptors, is being investigated as a treatment for depression, a psychiatric disorder with rising global prevalence projected to become the leading cause of disability by 2030. This narrative review presents recent reports on psilocybin-assisted therapy, which, based on promising results showing higher therapeutic efficacy compared to conventional treatments, offers hope for a modern approach with sustained clinical effects and minimal or no adverse effects.
Quality in Sport
January 31, 2026
Anna Maria Komarczewska, Filip Matusiak, Klaudia Brzoza et al.
Psilocybin-assisted interventions produce rapid reductions in depressive symptoms that can persist for months, including six-month outcomes in treatment-resistant depression protocols with psychological support. Convergent evidence from animal studies shows structural synaptic remodeling in frontal cortex and hippocampal plasticity changes in extinction learning paradigms. Human neuroimaging reveals altered large-scale brain dynamics after psilocybin. These findings support neuroplasticity as a biologically plausible mechanism linking transient serotonergic receptor activation to sustained clinical improvement.
Nature
January 28, 2026
Zheng Xu, Hongshuang Wang, Jingjing Yu et al.
5 citations
Psychedelics are being tested in over 200 clinical trials as potential treatments for psychiatric disorders, but how they work and their risks are not fully understood. The serotonin 2A receptor (5-HT2AR) is the main target of psychedelics. This study compared psychedelics with non-hallucinogenic analogues using cell and animal experiments, finding that 5-HT2AR signaling through a non-canonical Gi pathway is essential for hallucinogenic effects. Five cryo-electron microscopy structures of 5-HT2AR bound to these drugs were solved. A special contact between non-hallucinogenic analogues and the receptor biased signaling away from Gi. A derivative called DOI-NBOMe showed potent Gq-biased activity and therapeutic effects in mice without causing hallucinations. These findings reveal mechanisms of 5-HT2AR Gi signaling and guide the design of safer psychedelic-based drugs.
Journal of Medicinal Chemistry
January 26, 2026
Marco Banzato, Martina Colognesi, Lorena Lucatello et al.
A library of fluorinated reversible N-alkyl carbamate derivatives of psilocin was designed and synthesized to reduce acute psilocin exposure and limit hallucinogenic-like effects. By varying the number and positioning of fluorine atoms on the alkyl promoiety, carbamate bond stability was systematically modulated, yielding compounds with finely tuned hydrolysis under physiological conditions. A lead compound (4e) demonstrated favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. It exhibited intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects compared to psilocybin. Fluorinated carbamate chemistry provides a versatile platform to control psilocin exposure and serotonergic signaling.
International Journal of Innovative Technologies in Social Science
January 23, 2026
Jakub Klepacz, Radosław Swędrak, Marzena Swojnóg et al.
Classical serotonergic hallucinogens like psilocybin and LSD are being re-evaluated in clinical research. A systematic review traces their history from indigenous use through prohibition to current trials. The compounds act via 5-HT2A receptor agonism and disrupt the Default Mode Network, which may help alleviate rigid cognitive patterns in depression and anxiety. Clinical data show significant therapeutic potential for Treatment-Resistant Depression, end-of-life distress, and substance use disorders. The review emphasizes that psychedelic-assisted therapy requires a specific psychotherapeutic framework, integration processes, and attention to cost-effectiveness and access equity. This approach suggests a shift from chronic symptom management to rapid, episodic curative interventions if regulatory and ethical challenges are addressed.
Neuropharmacology
January 21, 2026
Ana Domi, Erika Lucente, Davide Cadeddu et al.
1 citation
Psilocin, the active metabolite of psilocybin, induces a long-lasting decrease in excitatory synaptic strength in the prefrontal cortex of rats, an effect that is independent of sex. This synaptic depression originates presynaptically and is not mediated by 5-HT2A or metabotropic glutamate group 2 receptors, but instead involves enhanced GABAergic inhibition. The effect is partially blocked by a 5-HT1A receptor antagonist and fully blocked by a TrkB receptor antagonist. These sustained changes in synaptic activity may relate to reduced prefrontal connectivity observed in humans and could affect cognitive function.
bioRxiv (Cold Spring Harbor Laboratory)
January 15, 2026
Justyna K. Hinchcliffe, Christopher W. Thomas, Gary Gilmour et al.
Psilocybin, a serotonergic psychedelic, can rapidly and lastingly reverse impaired reward processing in a rat model of depression. In rats with chronic interferon-alpha-induced depression, a single dose of psilocybin (0.3 mg/kg) restored reward-induced behavioral biases within 24 hours, and the effect persisted for at least 7 days. This suggests that restoring blunted reward processing may contribute to psilocybin's sustained antidepressant effects.
Journal of Psychopharmacology
January 6, 2026
Connor J. Maltby, Adam K. Klein, Enya Paschen et al.
3 citations
Psilocybin produces rapid and sustained antidepressant effects in major depressive disorder, but the underlying neurobiological mechanisms are unclear. In mice, psilocybin caused dose-dependent occupancy of the 5-HT₂A receptor in the prefrontal cortex, with an inverted-U dose-response for head twitch behavior peaking between 44% and 62% receptor occupancy. A 1.5 mg/kg dose increased time spent in open areas of the elevated zero maze, indicating reduced anxiety, while 3 mg/kg reduced immobility in the forced swim test, suggesting antidepressant-like effects. Both doses shifted α-tubulin post-translational modifications toward more dynamic microtubules and selectively increased synaptic protein expression in the prefrontal cortex, but not the amygdala. These findings indicate that psilocybin's therapeutic effects may involve dose- and region-specific enhancement of neuronal plasticity, with distinct signatures for anxiolytic-like and antidepressant-like properties.
ACS Chemical Neuroscience
January 2, 2026
Mario de la Fuente Revenga, Javier González-Maeso
1 citation
The subjective effects that define psychedelics like LSD, psilocybin, and DOI are linked to activation of the serotonin 2A receptor (5-HT2AR), but what differentiates psychedelic from nonpsychedelic 5-HT2AR agonists is unclear. A new ex vivo platform was developed to measure drug-mediated activation of the Gq/11 pathway in mouse brain tissue by tracking inositol monophosphate (IP1) levels. In the frontal cortex of mice, DOI produced time-bound, dose-dependent IP1 increases that correlated with head twitch responses. LSD elevated IP1, while lisuride did not, consistent with their respective psychedelic and nonpsychedelic natures. MDMA also increased IP1, attributed to serotonin release, unlike the serotonin precursor 5-HTP or fluoxetine. This method provides mechanistic insights into psychedelic action and Gq/11-coupled receptors.
Journal of Psychopharmacology
January 1, 2026
Petr Scholle, Štěpán Wenke, Tereza Nekovářová et al.
1 citation
Under psilocybin, healthy volunteers perceived time as moving more slowly and their temporal precision decreased, particularly for intervals longer than 2 seconds. In a double-blinded placebo-controlled study with 24 participants, the bisection point shifted rightward, indicating subjective time slowing, and the just noticeable difference increased, reflecting reduced accuracy. These changes were captured both by performance on the Temporal Bisection Task and by self-report scales. The findings suggest psilocybin disrupts cognitive functions such as working memory and attention, altering time perception through serotonergic system involvement.
Frontiers in pharmacology
January 1, 2026
Patricio Sáez-briones, Amanda Silva-Rodríguez, Michelle Morales-Vidal et al.
MDMA (Ecstasy) suppressed helping behavior in adult male rats at doses of 5 mg/kg and 10 mg/kg, fully eliminating the behavior, while lower doses (1 mg/kg and 0.5 mg/kg) caused partial inhibition only after the rats switched roles. The lowest dose (0.25 mg/kg) had no effect. Electrophysiological recordings showed that MDMA reinforced long-term depression in the nucleus accumbens core and increased long-term potentiation in the anterior cingulate cortex, with the latter depending on serotonin and oxytocin. These neuroplastic effects align with mechanisms thought to promote prosocial behavior, yet the drug disrupted helping behavior, suggesting MDMA may impair neural processes essential for executing helping actions without reducing the willingness to help.
Molecular pharmacology
January 1, 2026
Lindsay P Cameron, Alaina M Jaster, Raul A Ramos et al.
3 citations
2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic that binds tightly to 5-HT2 receptors, especially 5-HT2A and 5-HT2C. The US Drug Enforcement Administration proposed placing DOI and a similar compound in Schedule I of the Controlled Substances Act, citing their psychoactivity and potential for abuse. This review describes DOI's history, its essential role as a pharmacological tool in over 1,200 publications across five decades, and how it advanced the study of serotonin receptors. It also suggests alternative compounds for studying 5-HT2 receptors if DOI becomes restricted for research.
Figshare
January 1, 2026
Kristian Larsen
LSD occupies the serotonin 2A receptor (5-HT2AR) and alters global functional connectivity in healthy human participants. The figure shows occupancy and connectivity effects for both LSD and psilocybin. Acquisition, preprocessing, and statistical modeling procedures were pre-registered and detailed in a study protocol.
Online Publication Service of Würzburg University (Würzburg University)
January 1, 2026
Katja Ehrmann
Obsessive Compulsive Disorder (OCD) affects 2-3% of people, causing intrusive thoughts and repetitive behaviors that impair quality of life. Current treatments like cognitive behavioral therapy and SSRIs leave many patients unresponsive. Psilocybin, a psychedelic acting on serotonin receptors, may break rigid neural patterns and reset hyperactive brain networks. In a randomized placebo-controlled trial, participants with severe treatment-resistant OCD received up to 8 doses of psilocybin weekly, with doses varying from low to high. Psilocybin reduced OCD symptoms by 23% to 100%, with improvements lasting weeks to months. Higher doses produced stronger mystical experiences linked to greater symptom reduction. No severe side effects occurred. Despite clinical improvement, no changes in error-related brain activity were observed. Psilocybin appears promising for treatment-resistant OCD in a supportive setting.
OPUS FAU - Online publication system of Friedrich-Alexander-Universität Erlangen-Nürnberg
January 1, 2026
Aneta Petrušková
Serotonergic psychedelics LSD, psilocin, and DMT inhibit neurotransmission by reducing the proportion of synaptic vesicles that fuse in response to electrical stimulation after 3–30 minutes of treatment, an effect that disappears after 24 hours. DMT and psilocin increase evoked responses at glutamatergic synapses following single stimulation, while psilocin decreases paired-pulse facilitation. LSD and psilocin reduce evoked presynaptic calcium transients. At the network level, LSD and DMT strongly inhibit spontaneous neuronal firing without altering evoked responses. These findings expand understanding of the acute synaptic effects of psychedelics, though the link to therapeutic outcomes requires further research.
Psychopharmakotherapie
January 1, 2026
Antonia Bendau, Felix Betzler, Twyla Michnevich et al.
1 citation
Party drugs are a diverse group of legal and illegal psychoactive substances used in social settings like clubs and festivals to alter mood, perception, and social interaction. Alcohol and cannabis are most common, followed by amphetamine, MDMA, cocaine, and ketamine. These drugs act through various pharmacological mechanisms: alcohol affects GABAergic, glutamatergic, and dopaminergic systems; cannabis acts on the endocannabinoid system; stimulants increase monoaminergic neurotransmitters; MDMA has a strong serotonergic component; ketamine produces dissociative effects via glutamatergic mechanisms; and psychedelics alter sensory processing through serotonergic modulation. Polydrug use is frequent. Acute risks include cardiovascular strain, hyperthermia, and anxiety, while long-term consequences can involve cognitive impairments, dependence, and social complications.
Frontiers in pharmacology
January 1, 2026
Joseph Geraci, Erik Viirre, Bessi Qorri et al.
Classic psychedelics like LSD, psilocybin, and DMT affect perception and brain plasticity mainly by activating the 5-HT2A receptor and triggering calcium-dependent signaling. A speculative but testable hypothesis suggests these biochemical cascades might connect with quantum processes in the brain, specifically through nuclear spin dynamics in phosphate-based 'Posner molecules' (Ca9(PO4)6). Intense 5-HT2A-driven neural activity and calcium flux during psychedelic use could allow phosphorus nuclear spins in these molecules to become entangled and shielded from decoherence, later influencing neuronal signaling when the clusters release calcium. This framework, building on Fisher's quantum cognition model, proposes testable predictions and outlines short-, medium-, and long-term experiments to confirm or refute quantum involvement, which could transform understanding of mind-brain relationships and psychiatric treatment.